Clinical Trial Data Should Be Open for Review

Original clinical study reports, which contain far more detail than published randomized trials, should be made available to independent researchers seeking to verify efficacy and safety claims, a group of Cochrane reviewers argued.

In support of this argument, the history of the influenza antiviral oseltamivir (Tamiflu), which was approved by the FDA in 1999, was cited by Peter Doshi, PhD, from Johns Hopkins University in Baltimore, and colleagues in an article published online in PLoS Medicine.

In the run-up to the expected H1N1 influenza pandemic in 2009, the U.S. stockpiled a $1.5 billion supply of the drug to be used in case an outbreak occurred before a vaccine could be developed.

This action was done in light of claims by the Department of Health and Human Services that the antiviral would reduce hospitalizations, and by the Advisory Committee on Immunization Practices that its use could prevent disease complications.

The widespread belief in oseltamivir's efficacy, according to Doshi's group, was based on a meta-analysis of 10 trials conducted by the manufacturer prior to licensure.

The authors of that meta-analysis, which was published in 2003, suggested that the drug could reduce the likelihood of secondary complications. But the authors pointed out that the FDA, which was aware of these clinical trials, concluded that oseltamivir had not been shown to reduce complications and required a statement on the drug's label to that effect.

Moreover, oseltamivir was not given an FDA indication for prevention of spread of influenza.

To this, Doshi and colleagues commented, "If FDA is right, the drug's effectiveness may be no better than aspirin or acetaminophen."

The current authors requested the full clinical study reports from Roche, the manufacturer of oseltamivir, with the goal of independently scrutinizing all the available data. They reported receiving 3,200 pages in response.

They subsequently were able to obtain more data through a Freedom of Information request to the European Medicines Agency, but consider this just a fraction of the manufacturer's data.

Nonetheless, what they have learned from the original documents reviewed thus far included:

Serious adverse events that were not reported

Uncertainty about the validity of subgroup analyses

Contradictory claims on the drug's mode of action

"This information has turned our understanding of the drug's effects on its head," the researchers stated. "We challenge industry to either provide open access to clinical study reports or publicly defend their current position of [randomized controlled data]."

They further argued that the public should have access to full clinical study reports for ethical reasons.

Rofecoxib (Vioxx) and rosiglitazone (Avandia) are other drugs for which previously unpublished clinical trial data "radically changed public knowledge of safety and efficacy include," they said.

"We should not lose sight of the fact that clinical trials are experiments conducted on humans that carry an assumption of contributing to medical knowledge," they wrote.

However, a group of authors from several European regulatory agencies responded in a PLoS Medicine perspective article that there are valid reasons for not opening trial data up to the public.

First is the importance of patient confidentiality, which could be compromised, according to lead author Hans-Georg Eichler, MD, of the European Medicines Agency in London.

Secondly, they challenged the notion that so-called "independent" research groups are necessarily free of conflict of interest.

"Personal advancement in academia, confirmation of previously defended positions, or simply raising one's own visibility within the scientific community may be powerful motivators," wrote Eichler and colleagues, also in PLoS Medicine.

Furthermore, unrestricted availability of data could lead to promulgation of misleading information and possible health scares among the public.

The regulators suggested several steps that could help resolve these conflicts, such the establishment of adequate, but not excessive, standards of protection for patients and quality requirements for meta-analyses.

They also called for openness not only on the part of industry, investigators, and regulators, but also on the part of those who conduct independent data re-analyses.

The authors have received a UK National Institute for Health Research grant to undertake a Cochrane review of neuraminidase inhibitors.

One co-author was an ad hoc advisor for F. Hoffman-La Roche Ltd, and has been retained as a consultant in a legal case involving Tamiflu.

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